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Anti-PD-L1 Lead-in Before MAPKi Combination Maximizes Anti-Tumor Efficacy and Immunity.

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE177902 | GEO | 2021/08/19

REPOSITORIES: GEO

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Anti-PD-L1 Lead-in Before MAPKi Combination Maximizes Anti-Tumor Efficacy and Immunity [TCRseq]

Project description:Indications of PD-1/L1- and MAPK-targeted therapies cross cancer histologies. Rationally sequencing and/or combining them may overcome innate and acquired resistance. We observed increased clinical benefit of BRAF andV600MUT/MEK inhibitors in patients with advanced BRAFV600MUT melanoma who were previously treated with immune checkpoint therapy (ICT). To test whether ICT primes MAPK inhibitor (MAPKi) efficacy, we compared sequential/combinatorial regimens in subcutaneous mouse tumors driven by BrafV600, Nras, Nf1 or Kras mutations. The most efficacious regimen consisted of anti-PD-L1 lead-in preceding MAPKi combination and specifically promoted intratumoral pro-inflammatory macrophages and clonal expansion of IFNhi, CD8+ cytotoxic T-cells (relative to CD4+ regulatory T-cells) that highly expressed activation and cytolytic genes. Since melanoma brain metastasis (MBM) and its propensity for therapeutic resistance limit patient survival, we developed an experimental metastasis model of BrafV600MUT MBM. Sequencing anti-PD-L1 before MAPKi combination resulted in superior MBM control and survival as well as robust intratumoral T-cell clonal expansion both intracranially and extracranially. We propose that brief anti-PD-1/L1 dosing prior to MAPKi co-treatment suppresses resistance.

2021-08-19 | GSE177900 | GEO

Anti-PD-L1 Lead-in Before MAPKi Combination Maximizes Anti-Tumor Efficacy and Immunity [scRNAseq and scTCR-seq]

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Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy.

Project description:Rationally sequencing and combining PD-1/L1-and MAPK-targeted therapies may overcome innate and acquired resistance. Since increased clinical benefit of MAPK inhibitors (MAPKi) is associated with previous immune checkpoint therapy, we compare the efficacies of sequential and/or combinatorial regimens in subcutaneous murine models of melanoma driven by BrafV600, Nras, or Nf1 mutations as well as colorectal and pancreatic carcinoma driven by KrasG12C. Anti-PD-1/L1 lead-in preceding MAPKi combination optimizes response durability by promoting pro-inflammatory polarization of macrophages and clonal expansion of interferon-γhi, and CD8+ cytotoxic and proliferative (versus CD4+ regulatory) T cells that highly express activation genes. Since therapeutic resistance of melanoma brain metastasis (MBM) limits patient survival, we demonstrate that sequencing anti-PD-1/L1 therapy before MAPKi combination suppresses MBM and improves mouse survival with robust T cell clonal expansion in both intracranial and extracranial metastatic sites. We propose clinically testing brief anti-PD-1/L1 (± anti-CTLA-4) dosing before MAPKi co-treatment to suppress therapeutic resistance.

| S-EPMC9126729 | biostudies-literature

Anti-PD-L1 Lead-in Before MAPKi Combination Maximizes Anti-Tumor Efficacy and Immunity.

Project description:Anti-PD-L1 Lead-in Before MAPKi Combination Maximizes Anti-Tumor Efficacy and Immunity.

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Anti-PD-L1 Lead-in Before MAPKi Combination Maximizes Anti-Tumor Efficacy and Immunity [TCRseq]

Project description:Anti-PD-L1 Lead-in Before MAPKi Combination Maximizes Anti-Tumor Efficacy and Immunity [TCRseq]

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Anti-PD-L1 Lead-in Before MAPKi Combination Maximizes Anti-Tumor Efficacy and Immunity [scRNAseq and scTCR-seq]

Project description:Anti-PD-L1 Lead-in Before MAPKi Combination Maximizes Anti-Tumor Efficacy and Immunity [scRNAseq and scTCR-seq]

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Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy.

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Project description:T follicular helper cells (Tfh) are essential to shape B cell response during germinal center formation. Tfh accumulation has been reported in various human cancers, with positive or negative prognostic roles. However, the mechanisms explaining the accumulation of Tfh and their role in cancer remain obscure. In vitro differentiated and mouse cell sorted Tfh phenotype was evaluated by flow cytometry and quantitative PCR (qPCR). Antitumor effect of Tfh was evaluated by adoptive transfer in different tumor-bearing mice models. The involvement of immune cells, cytokines and chemokines was evaluated, using depleting antibodies. Chemokines and cytokines expression and production were evaluated by qPCR and ELISA. In human, the impact of immune cells and chemokines on survival was evaluated by analyzing transcriptomic data from public databases and from our own patient cohorts. In this study, we show that Tfh exert an antitumor immune effect in a CD8+-dependent manner. Tfh produce interleukin-21, which sustains proliferation, viability, cytokine production and cytotoxic functions of exhausted T cells. The presence of Tfh is required for efficacy of antiprogrammed cell death ligand-1 therapy. Tfh accumulate in the tumor bed and draining lymph nodes in different mouse cancer models. This recruitment is due to the capacity of transforming growth factor β to drive Chemokine (C-X-C motif) Ligand 13 expression, a chemoattractant of Tfh, by intratumor CD8+ T cells. Accumulation of Tfh and exhausted CD8+ T cells predicts cancer outcome in various cancer types. In patients treated with anti-programmed cell death-1 mAb, accumulation of Tfh and CD8+ at the tumor site is associated with outcome. This study provides evidence that CD8+/Tfh crosstalk is important in shaping antitumor immune response generated by immunotherapy.

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Dual checkpoint blockade of CD47 and PD-L1 using a novel affinity-tuned bispecific antibody maximizes anti-tumor immunity

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-10-15 | GSE180297 | GEO

Dual checkpoint blockade of CD47 and PD-L1 using a novel affinity-tuned bispecific antibody maximizes anti-tumor immunity (NanoString)

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